Dialkyl substituted amides of



Patented Apr. 26, 1938 UNITED STATES PATENT OFFICE DIALKYL SUBSTITUTEDAMIDES OF ISOXAZOLE GARBOXYLIC ACIDS Max Hofier, Basel, Switzerland,assignor to Hoffmann-La Roche Inc Nutley, N. J., a corporation of NewJersey No Drawing. Application February 4, 1936, Se-

rial No. 62,381. In 1935 6 Claims.

in which one of the radicles R1, R2, R3 represents a carboxyl group, theothers alkyl radicles or hydrogen, are transformed into reactive acidderivatives, for instance into the so far unknown acid chlorides, andthese caused to react with secondary amines.

The new isoxazole carboxylic acid dialkylamides are compounds soluble inWater, alcohol, ether, chloroform, benzene. They are to be used asmedicines.

Example 1 140 parts by weight of 3,5-dimethyl-isoxazole- 4-carboxylicacid (Annalen der Chemie, vol. 277, 1893, page 174) are boiled with 400parts by weight of thionyl chloride for 1 hours under reflux. The excessof thionyl chloride is distilled off on the steam-bath and the residuedistilled in vacuo. The dimethyl-isoxazole-carboxylic acid chloride is acolourless oil which boils at 90 C. under a pressure of 12 mm.

158 parts by weight of 3,5-dimethyl-isoxazole- 4-carboxylic acidchloride are diluted with 300 parts by weight of ether; while stirringand thoroughly cooling '75 parts by weight of diethylamine are slowlyadded. To the reaction product which, owing to the precipitation ofdiethylamine hydrochlorideis transformed into a pulp, 200 parts byweight of a 20% solution of sodium hydroxide are slowly added whilethoroughly stirring and cooling, whereby the reaction between thediethylamine and the acid chloride is completed. Finally the samequantity by volume of a 20% solution of sodium hydroxide is added andthe aqueous layer is removed. After drying with solid potassiumhydroxide and remov- Germany February 22,

ing the ether by distillation the diethylamide of3,5-dimethyl-isoxazole-4-carboxylic acid is obtained which has theformula:

CCH: i

For purification the product is distilled in vacuo. The compound is analmost colourless oil boiling at 155156 C. under a pressure of 11 mm. Itis miscible in all proportions with Water, alcohol,

ether, chloroform, benzene, but diflicultly soluble in petroleum ether.

Example 2 158 parts by weight of 3,5-dimethyl-isoxazolei-carboxylic acidchloride are heated with 80 parts by Weight of dimethylaminehydrochloride in an oil-bath to 130140 C. until the evolution ofhydrochloric acid ceases. After cooling the product is dissolved in alittle water and the dimethylamide of3,5-dimethyl-isoxazole-4-carboxylic acid precipitated by the addition ofa 30% solution of potassium hydroxide. The product is taken up withether, dried with solid potassium hydroxide and purified by distillingin vacuo. The compound forms colourless prisms melting at 0.; it iseasily soluble in water, alcohol, ether, chloroform and benzene,difiicultly soluble in petroleum ether. This compound has the formula:

127 parts by weight of 5-methyl-isoxazole-3- oarboxylic acid (Berichteder Deutschen Chemischen Gesellschaft, vol. 42, 1909, page are mixedwith 207 parts by Weight of phosphorus pentachloride. The mixturequickly liquefies with Vigorous evolution of hydrogen chloride. Afterwarming for half an hour on the Waterbath under reflux the conversionwill be completed. By fractionally distilling in vacuo the5-methyl-isoxazole-S-carboxylic acid chloride is obtained in pure form.It is a colourless oil which distils under a pressure of 14 mm. at 82-84C. On cooling to 0 C. it sets to an aggregate of colourless needlesmelting at 25 C.

144 parts by weight of 5-methyl-isoxazole-3- carboxylic acid chlorideare caused to react with '7 5 parts by weight of diethylamine in themanner described in Example 1. The diethylamide of 5- methyl-isoxazole-3-carboxylic acid thus obtained boils under a pressure of 13 mm. at146-148 C. and forms a colourless oil, which dissolves at roomtemperature in about the 20-fold quantity of water. In alcohol, ether,benzene or chloroform the compound is easily soluble. This compound hasthe formula:

Example 4 144 parts by weight of B-methyl-isoxazole-3- carboxylic acidchloride are reacted with parts by weight of dimethylamine hydrochloridein the manner described in Example 2. The dimethylamide of5-methyl-isoXazole-3-carboxylic acid is a light-coloured oil boiling at142-143 C. It is miscible in all proportions with water, alcohol, ether,chloroform and benzene. This compound has the formula:

The heretofore unknown 3- or S-methyl-isoxazole-4-carboxylic acid isobtained by treating ethoxymethylene acetic acid ester withhydroxylamine. The ester is saponified by boiling with dilute mineralacid. The 3- or S-methyl-isoxazole-carboxylic acid crystallizes fromwater in colourless prisms melting at 143-144 C. From the method offormation it is not possible to decide with absolute certainty which ofthe two possible constitutions, that of the 3- or that of theS-methyl-isoxazole-4-carboxylic acid, pertains to the acid obtained.

127 parts by weight of 3- or 5-methy1-isoxazole-4-carboxylic acid areconverted into the chloride in the manner described in Example 3 bymeans of 207 parts by weight of phosphorous pentachloride. The 3- or5-methyl-isoxazolecarboxylic acid chloride is a colourless oil boilingunder a pressure of 13 mm. at 83-84 C.

144 parts by weight of the chloride are reacted with parts by weight ofdiethylamine as described in Example 1. The diethylamide ofmethyl-isoxazole-4-carboxylic acid is a lightcoloured oil boiling at146-148 C. under a pressure of 12 mm. It'is rather difiicultly solublein water, easily soluble in ether, chloroform and benzene. This compoundhas the formula:

158 parts by Weight of 3,5-dimethyl-isoxazole-4- carboxylic acidchloride are diluted with the same quantity of ether. While stirring andcooling 97 parts by weight of diallylamine in parts by weight of etherare dropped in. When all the acid chloride has been added, 200 parts byweight of a 20% solution of sodium hydroxide are allowed to flow inwhile stirring and cooling. The precipitated diallylamine hydrochlorideis thus dissolved and completely converted. Then the ether layer isremoved and the product dried with anhydrous potassium carbonate. Whenthe ether has been removed by distillation the3,5-dimethyl-isoxazole-4-carboxylic acid diallylamide remains and may bepurified by distilling in vacuo. The compound is a light-yellow oilwhich boils at 166-16'7 C. under a pressure of 13 mm. It is misciblewith alcohol, ether, benzene, chloroform, insoluble in petroleum ether.In water it is difiicultly soluble at room temperature. This compoundhas the formula:

Example 7 156 parts by Weight of diethylamino-ethylallylamine aredissolved in 200 parts by weight of benzene and 500 parts by weight of a10% solution of sodium hydroxide are added. 158 parts by weight of3,5-dimethyl-isoxazole-4-carboxylic acid chloride are dropped in whilethoroughly stirring and cooling. The benzene layer is dried withpotassium carbonate, the benzene evaporated and the residue distilled invacuo. The 3,5-dimethyl-isoxazole-4-carboxylic aciddiethylamino-ethylallylamide boils at 200-202 C. under a pressure of 13mm. It is easily soluble in organic solvents with the exception ofpetroleum ether. In water it dissolves at room temperature to the extentof about 8%. This compound has the formula:

In the same manner may be obtained the 3,5-dnnethyl-isoxazole-4-carboxylic acid di-n-propylamide, a light-yellow,rather diilicultly water-soluble oil melting at 168-170 C. under 13 mm.pressure, and the 3,5dimethyl-isoXazole-4-carboxylic aciddi-n-butylamide, a diflicultly water-soluble yellow oil boiling at182-l84 C. under 13 mm. pressure.

I claim:

1. As a new analeptic, a compound of the general formula R1(|3/ om 0 1twherein one of the radicals R 11. and R represents the group wherein Xrepresents a lower aliphatic radical and Y is a radical selected fromthe group consisting of lower alkyl and lower .dialkyl amino.

lower alkyl radicals, the remaining R radicals being selected from thegroup consisting of hydrogen and alkyl radicals, said compound beingsoluble in water and suitable for oral and parenteral administration.

2. As a new analeptic, a compound of the general formula wherein R and Rare selected from the group consisting of hydrogen and alkyl radicals, Xrepresents a lower aliphatic radical and Y is a radical selected fromthe group consisting of lower alkyl and lower dialkyl amino lower alkylradicals, said compound being soluble in water and suitable for oral andparenteral administration.

3. As a new analeptic, the compound. 3,5-dimethyl-isoxazole-4carboxylicacid diethylamide having the structure CON (5 cz t CHFC Ell-CH:

which is soluble in water and suitable for oral and parenteraladministration.

4. As a new analeptic, the compound 3,5-dimethyl-'isoxazole-4-diethylaminoethylallylamide having the structure which issoluble in water and suitable for oral and parenteral administration.

5. As a new analeptic a compound of the gen eral formula R2 )1 R -C\C-CO-N/ I ll ON Y wherein R and R. are selected from the groupconsisting of hydrogen and alkyl: radicals, X represents a loweraliphatic radical and Y is a radical selected from the group consistingof lower alkyl and lower dialkyl amino lower alkyl radicals, saidcompound being soluble in water and suitable for oral and parenteraladministration.

6. As a new analeptic the compound 5-methylisoxazole-3-carboxylic aciddiethylamide having the formula which is soluble in water and suitablefor oral and parenteral administration.

MAX HOFFER

